Integrative genetic and multi-omics analysis reveals the interleukin-6 receptor's role in recurrent spontaneous abortion.

Background: Recurrent spontaneous abortion (RSA) significantly impacts women's health, yet the underlying biological mechanisms remain poorly defined. Understanding the molecular contributors to RSA is crucial for developing targeted interventions. Objective: This study aims to investigate the causal relationships between plasma proteins and RSA, focusing on the identification of potential therapeutic targets through multi-omic approaches. Methods: We utilized two-sample Mendelian randomization (MR) analyses integrating genome-wide association study (GWAS) data for both plasma proteins and RSA. Proteomic data were sourced from the UK Biobank-Plasma Proteome Project and deCODE Health Study. We further validated our findings through both bulk and single-cell RNA sequencing of clinical specimens, alongside quantitative real-time polymerase chain reaction and immunohistochemistry. A phenome-wide association study was also conducted to assess the safety and broader implications of identified targets. Results: Our analyses identified the interleukin 6 receptor (IL6R) as a key candidate, with elevated plasma levels correlating with increased RSA risk. Furthermore, IL6R was found to be upregulated in RSA-related endometrial and decidual tissues. The phenome-wide association study provided insights into potential side effects and additional therapeutic indications for IL6R. Conclusion: IL6R upregulation is mechanistically implicated in the pathogenesis of RSA, establishing it as a validated causal biomarker and a potentially actionable therapeutic target. This study not only highlights the role of IL6R in RSA but also supports its development into a therapeutic strategy with a comprehensive safety profile.